CN113456659B - Composition of tiliroside and sorafenib and application of composition in preparation of anti-liver cancer drugs - Google Patents
Composition of tiliroside and sorafenib and application of composition in preparation of anti-liver cancer drugs Download PDFInfo
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- CN113456659B CN113456659B CN202110807597.0A CN202110807597A CN113456659B CN 113456659 B CN113456659 B CN 113456659B CN 202110807597 A CN202110807597 A CN 202110807597A CN 113456659 B CN113456659 B CN 113456659B
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Abstract
The invention discloses a composition of tiliroside and sorafenib and application of the composition in preparation of anti-liver cancer drugs. The experimental result shows that the tiliroside and sorafenib can effectively inhibit the activity of liver cancer cells independently, and the combination of the tiliroside and sorafenib can synergistically inhibit the activity of liver cancer cells, so that the tiliroside and sorafenib have the prospect of being developed into an anti-liver cancer pharmaceutical composition.
Description
Technical Field
The invention belongs to the field of medicines, relates to a pharmaceutical composition and application thereof, and in particular relates to a composition of tiliroside and sorafenib and application thereof in preparing anti-liver cancer drugs.
Background
According to the statistics report of the world health organization/the international cancer research institution, the number of new cases of liver cancer in 2020 worldwide is 905677, the coarse incidence is 11.6/10 ten thousand, and the world standardized incidence is 9.5/10 ten thousand. The global liver cancer death rate of 2020 is 830180 cases, the coarse death rate is 10.7/10 ten thousand, and the world population standardized death rate is 8.7/10 ten thousand. Asian area is the area with highest incidence rate of liver cancer in five continents worldwide, and accounts for 72.5% of the global liver cancer incidence rate.
Sorafenib, a small molecule multi-kinase inhibitor, is the only approved drug currently used for treating patients with advanced hepatocellular carcinoma, and inhibits tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis by inhibiting serine-threonine kinase (Raf-1) and receptor tyrosine kinase activity of Vascular Endothelial Growth Factor Receptors (VEGFRs) and interfering with cell signaling pathways mediated by Raf-1 and VEGFRs pathways. Although sorafenib can extend the median survival time in advanced HCC patients, this benefit is reduced by the development of sorafenib resistance by tumor cells, ultimately resulting in treatment failure (literature: progress in the study of the mechanism of sorafenib's treatment of hepatocellular carcinoma resistance to liver cancer, journal of the medical college of Gannan, volume 41, 4 of 2021).
The search of a pharmaceutical composition with synergistic anti-liver cancer effect with sorafenib is an important way for improving the anti-liver cancer effect of sorafenib. Miao Jiuwang, et al found that celecoxib enhanced the anti-hepatoma HepG2 cell proliferation effect of sorafenib (literature: celecoxib combined with sorafenib affects human hepatoma HepG2 cell migration and invasiveness), clinical medicine research and practice, volume 6, phase 7 of 2021). Li Yanling and the like find that both sorafenib and ipilimumab can significantly inhibit proliferation and invasion of liver cancer HepG2 cells, are related to inhibiting Raf-1/MEK1/ERK1 signal paths, and are superior to single drugs in combined administration (literature: experimental study of the inhibition of liver cancer by sorafenib combined with ipilimumab, cancer progression, volume 19, 7 of 2021). Su Yuehua, etc., find that the paclitaxel and sorafenib have remarkable effects on treating middle and late liver cancer, and are superior to the independent curative effects of sorafenib (literature: analysis of the effects of paclitaxel and sorafenib on treating middle and late liver cancer, contemporary medicine, volume 26, 4 of 2020).
The invention is particularly proposed for finding out more components with synergistic anti-liver cancer effect with sorafenib.
Disclosure of Invention
The invention aims to provide a composition of tiliroside and sorafenib and application of the composition in preparation of anti-liver cancer drugs.
The above object of the present invention is achieved by the following technical scheme:
a pharmaceutical composition comprises tiliroside and sorafenib.
Preferably, the molar ratio of tiliroside to sorafenib is 5:1.
The application of the pharmaceutical composition in preparing anti-liver cancer drugs.
The beneficial effects are that:
the experimental result shows that the tiliroside and sorafenib can effectively inhibit the activity of liver cancer cells independently, and the combination of the tiliroside and sorafenib can synergistically inhibit the activity of liver cancer cells, so that the tiliroside and sorafenib have the prospect of being developed into an anti-liver cancer pharmaceutical composition.
Drawings
FIG. 1 shows the results of measuring the cell viability of liver cancer cells of each group of tiliroside;
FIG. 2 shows the results of cell viability assays for various groups of liver cancer cells of sorafenib;
FIG. 3 shows the results of cell viability assay of liver cancer cells of each combination;
fig. 4 shows results of the combination index CI of tiliroside and sorafenib given by the software, wherein a is Combination Index Plot, B is Logarithmic Combination Index Plot, and C is the ED50 synergy index.
Detailed Description
The following describes the essential aspects of the invention in detail with reference to the drawings and examples, but is not intended to limit the scope of the invention.
1. Experimental materials
And (3) cells:
| cells | Source |
| HepG2 | Cell bank of Shanghai department of science |
| Hep3B | Cell bank of Shanghai department of science |
Reagent consumable:
| DMEM medium | Hclone |
| RPMI medium | Hclone |
| Fetal bovine serum | AusGenex |
| pancreatin-EDTA | Solarbio |
| CCK8 | Sigma |
| Penicillin-streptomycin | Gibco |
| Tiliaside (Tilroside; til) | Shanghai Nature Standard R&D and Biotech Co.,Ltd. |
| Sorafenib (Sorafenib; sor) | Selleck |
2. Experimental method
1. Cell culture
Liver cancer HepG2 and Hep3B cells were cultured in DMEM containing 10% FBS, 100U/ml penicillin, 100 μg/ml streptavidin, respectively, based on 5% CO 2 Culturing in an incubator at 37 ℃ for every 2-3 d passage.
2. Grouping and administration
Tilia mandshurica glycoside group: 25, 50, 100, 150, 200, 250, 300. Mu.M tiliroside, respectively;
sorafenib group: 5, 10, 20, 30, 40 μm of sorafenib, respectively;
combination group: tilia candel + sorafenib were administered at 25+5, 50+10, 100+20, 150+30, 200+40, respectively.
3. Determination of cell viability and calculation of IC50 values
Taking each tumor cell in logarithmic growth phase, re-suspending with corresponding culture medium to obtain cell suspension, inoculating into 96-well culture plate, adding 100 μl of the culture medium into each well to obtain cell density of 5000 cells/well, and adding 5% CO 2 Culturing in an incubator at 37 ℃. After 12h incubation, different concentrations of drug were prepared using fresh medium and the medium was changed so that the final drug concentration was 6 wells per concentration as indicated by the above-described groupings. Meanwhile, cells cultured without adding medicines are set as a control group, and culture solution without cells is set as a blank group. After further culturing for 24, 48 and 72 hours, 10 mu LCCK8 solution is added into each hole for further culturing for 2 hours, the light absorption value of each hole is measured at the wavelength of 450nm of the ELISA tester, and the survival rate of each group of cells is calculated according to the following formula: cell viability (%) = [ (OD drug group-OD blank)/(OD control group-OD blank)]X 100%. IC50 values of the drug for each tumor cell were calculated using GraphPadPrism6 software.
4. Collaborative discrimination method
The combined index (combination index, CI) for the combination of tiliroside and sorafenib was calculated using the medium effect method using the Compusyn software. According to Soriano et al (document: synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer Res,1999; combination of the buck grass and the poria cocos for inhibiting invasion and metastasis of breast cancer cells and preliminary mechanism research, chinese pharmacological notification, 2017), CI is more than or equal to 0.9 and less than or equal to 1.1 and is additive, CI is more than or equal to 0.8 and less than or equal to 0.9 and is low-degree synergistic, CI is more than or equal to 0.6 and less than or equal to 0.8 and is moderate-degree synergistic, CI is more than or equal to 0.4 and is less than or equal to 0.6 and is high-degree synergistic, and CI is more than or equal to 0.2 and less than or equal to 0.4 and is strong synergistic.
5. Statistical method
Statistical analysis was performed using GraphPad Prism6 and the combination index was calculated using Compusyn software. Experimental result data
The data obtained from the experiment were tested using Student's t test, p < 0.05, and differences were considered statistically significant. * Or #p < 0.05, # p < 0.01.
3. Experimental results
1. Influence of Tilia Miqueliana Maxim on liver cancer cell viability
The cell viability measurement results of liver cancer cells of each group of tiliroside are shown in figure 1, and tiliroside can effectively inhibit the viability of liver cancer HepG2 and Hep3B cells, and has obvious dose-dependent effect and time-dependent effect.
IC50 values of the inhibiting effect of tiliroside on liver cancer HepG2 and Hep3B under different action time are shown in table 1.
TABLE 1 IC50 values of Tilia Miqueliana glycosides inhibiting liver cancer HepG2, hep3B at different time of action
2. Influence of sorafenib on liver cancer cell viability
The result of measuring the cell viability of each group of liver cancer cells of sorafenib is shown in fig. 2, so that sorafenib can effectively inhibit the viability of liver cancer HepG2 and Hep3B cells, and has obvious dose-dependent effect.
The IC50 values of 24h sorafenib inhibition on liver cancer HepG2 and Hep3B are shown in Table 2.
TABLE 2 IC50 values for 24h action of Sorafenib on liver cancer HepG2, hep3B inhibition
| IC50(μM) | |
| HepG2+sorafenib | 20.04 |
| Hep3B+ sorafenib | 22.46 |
3. Influence of the composition on the viability of liver cancer cells
The cell viability measurement results of each group of liver cancer cells are shown in figure 3, and the combined drug can effectively inhibit the viability of liver cancer HepG2 and Hep3B cells and show obvious dose-dependent effect; as can be seen from fig. 3, the inhibition intensity of the combined drug on the viability of the liver cancer cells is significantly higher than that of the single drug.
The combination index CI results given according to the CompuSyn software are shown in FIG. 4 and Table 3, where A is Combination Index Plot, B is Logarithmic Combination Index Plot, and C is the ED50 synergy index in FIG. 4.
TABLE 3 combination index CI results
| HCC cells | CI | Whether or not there is a synergistic effect |
| HepG2 | 0.71690 | Is that |
| Hep3B | 0.85689 | Is that |
The experimental results show that the tiliroside and sorafenib can effectively inhibit the activity of liver cancer cells independently, and the combination of the tiliroside and sorafenib can synergistically inhibit the activity of liver cancer cells, so that the tiliroside and sorafenib have the prospect of being developed into an anti-liver cancer pharmaceutical composition.
The above-described embodiments serve to describe the substance of the present invention in detail, but those skilled in the art should understand that the scope of the present invention should not be limited to this specific embodiment.
Claims (2)
1. A pharmaceutical composition characterized by: consists of tiliroside and sorafenib, wherein the molar ratio of tiliroside to sorafenib is 5:1.
2. Use of the pharmaceutical composition of claim 1 for preparing an anti-liver cancer drug.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001247470A (en) * | 2000-03-03 | 2001-09-11 | Morishita Jintan Kk | Agent for protecting liver |
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| WO2013119825A1 (en) * | 2012-02-07 | 2013-08-15 | De Benedetti Arrigo | Modulators of tousled kinase in cellular processes |
| CN111265539B (en) * | 2020-03-19 | 2021-05-18 | 暨南大学 | Application of tiliroside in preparation of anti-influenza drugs |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001247470A (en) * | 2000-03-03 | 2001-09-11 | Morishita Jintan Kk | Agent for protecting liver |
Non-Patent Citations (3)
| Title |
|---|
| Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib;C. Yang et al;Phytomedicine;第111卷;第1-14页 * |
| 南蛇藤提取物抑制人胃癌MGC-803细胞生长的作用机制;彭微 等;中国社区医师;第35卷(第30期);第7-8页 * |
| 银椴苷抑制人胰腺癌细胞增殖的作用及机制研究;仲维兰 等;中国药理学通报;第24卷(第12期);第1679-1683页 * |
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